Addison's disease is a rare disease, wherein the adrenals can not produce sufficient steroid hormones (cortisol and aldosterone). Patients with Addison's disease report impaired subjective health status, and they have increased all-cause mortality. Conventional therapy is by oral replacement of glucocorticoid and mineralocorticoid hormones, but this strategy imperfectly mimic the diurnal cortisol variations, and render the patients both over- and under-treated. Anecdotally, some patients with adrenal insufficiency may benefit from the use of various nutritional compounds. We hypothesised that liquorice and grapefruit altered the metabolism and absorption of cortisone acetate.

AUC Serum Cortisol - Levels of cortisol in serum during the first 2.6 hours after oral administration of cortisone acetate. [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

The area under the curve (AUC) of cortisol is calculated based on serum time-series sampling (every 20 minutes for 2.6 h after oral administration of cortisone acetate). The AUCs obtained during liquorice and grapefruit juice intakes are compared to the baseline assessment (without these nutritional compounds). All other pharmacokinetic properties (primary and secondary outcome measures) are compared analogously.

Secondary Outcome Measures:

Serum Cortisol levels at the end of time-series sampling (t=160min) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments

Serum Cortisone levels at the end of time-series sampling (t=160min) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments

Saliva Cortisol levels at the end of time-series sampling (t=160min) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments

Saliva Cortisone levels at the end of time-series sampling (t=160min) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

At the end of time series sampling (160 minutes after orally administered cortisone acetate) on all three assessments

Time of maximum concentration of serum Cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

Based on time-series sampling at each of the three assessments

Time of maximum concentration of serum Cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

Based on time-series sampling at each of the three assessments

Time of maximum concentration of Saliva Cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

Based on time-series sampling at each of the three assessments

Time of maximum concentration of Saliva Cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

Based on time-series sampling at each of the three assessments

Half life of serum cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

Based on time-series sampling at each of the three assessments

Half life of serum cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

Based on time-series sampling at each of the three assessments

Urinary aTHF/THF-ratio [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

Measured in 24h urine obtained at the three assessments.

aTHF = allo-tetrahydrocortisol, THF = tetrahydrocortisol

AUC Serum Cortisone [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

Similar to primary outcome Serum AUC Cortisol

Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

Urinary Ratio Cortisol/6beta-OH-Cortisol [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

Assess the enzymatic activity of CYP3A4 by the index urinary cortisol/6beta-oh cortisol ratio obtained at the three assessments (baseline, after liquorice and after grapefruit juice.

6OHF = 6beta-hydroxycortisol

Urine total metabolites (Urinary cortisol+cortisone+6OHF+aTHF+THF+THE) [ Time Frame: Outcome measures are assessed when all subjects have completed the study, approximately 1.5-2.0 years after study start. ] [ Designated as safety issue: No ]

200 ml pink grapefruit juice three times a day. Results are compared to a baseline assessment without liquorice/grapefruit juice ingestion.

Dietary Supplement: Grapefruit Juice

200 ml pink grapefruit juice three times a day, taken orally, for three days.

No Intervention: Baseline

Baseline assessment without intake of liquorice or grapefruit juice

Detailed Description:

In the present study, cortisone acetate absorption and metabolism are assessed in subjects with Addison's disease on three occasions. On the first occasion, the subjects are on their regular diet, but avoid ingestion of grapefruit and liquorice. At the end of the baseline assessment the order of the nutritional compounds (liquorice-grapefruit juice or grapefruit juice-liquorice) to be investigated in the next two assessments are randomised.

On the two next occasions, the absorption and metabolism of cortisone acetate is studied when study subjects consume liquorice and grapefruit juice. Between the use of grapefruit and liquorice there is a wash out period of at least 3 weeks.

For studies on liquorice effects, the subjects ingest 24-gram liquorice per day (equivalent of 150-mg glycyrrhizinic acid per day). For studies on grapefruit juice effects, subjects drink 200-ml grapefruit juice three times a day for three days. They maintain their regular medication and usual diet.

Time-series of cortisol and cortisone are obtained in serum and saliva samples on the third day of liquorice/grapefruit juice use. 24-hour urine is also collected.

Measurements of cortisol and metabolites in serum and saliva are used to calculate pharmacokinetical parameters. The measurements from samples obtained when using the investigated nutritional compounds are compared to the baseline assessment in each subject. Metabolites in 24-hour urine are compared similarly to investigate changes in urinary excretion, and to estimate the activity of enzymes involved in the metabolism of cortisol (5alfa-reductase, 5beta-reductase, cytochrome P450 3A4 system, 11-beta hydroxysteroid dehydrogenase).

Eligibility

Ages Eligible for Study:

18 Years to 80 Years

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Verified diagnosis of adrenal insufficiency (Addison's disease)

Stable cortisone acetate replacement therapy

Written informed consent

Exclusion Criteria:

Malignant disease

Pharmacological treatment with other glucocorticoids

Pregnancy

Current minor disease (ie the flu)

Major disease or accident requiring hospitalization the last three months

Use of grapefruit juice or liquorice the last two weeks before study start

Blood pressure above 150mmHg systolic or 90 mmHg diastolic.

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01271296

Locations

Norway

Haukeland University Hospital, Helse-Bergen HF

Bergen, Norway, 5020

Sponsors and Collaborators

Haukeland University Hospital

Investigators

Principal Investigator:

Paal Methlie, MD

University of Bergen. Helse-Bergen HF

Principal Investigator:

Kristian Løvås, MD, PhD

University of Bergen. Helse-Bergen HF.

Principal Investigator:

Eystein S Husebye, Prof, MD

University of Bergen. Helse-Bergen HF.

Principal Investigator:

Ernst A Lien, Prof. MD.

University of Bergen

More Information

No publications provided

Responsible Party:

Lars Birger Nesje, Head of Department of Medicine, Haukeland University Hospital, Helse-Bergen HF, Haukeland University Hospital